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WO2018157842A1 - Use of 2-(substituted phenylamino)benzoic acid fto inhibitor in treating leukemia - Google Patents

Use of 2-(substituted phenylamino)benzoic acid fto inhibitor in treating leukemia Download PDF

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Publication number
WO2018157842A1
WO2018157842A1 PCT/CN2018/077789 CN2018077789W WO2018157842A1 WO 2018157842 A1 WO2018157842 A1 WO 2018157842A1 CN 2018077789 W CN2018077789 W CN 2018077789W WO 2018157842 A1 WO2018157842 A1 WO 2018157842A1
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group
compound
salt
pharmaceutical composition
pharmaceutically acceptable
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PCT/CN2018/077789
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French (fr)
Chinese (zh)
Inventor
杨财广
黄悦
董泽
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中国科学院上海药物研究所
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Publication of WO2018157842A1 publication Critical patent/WO2018157842A1/en

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    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Definitions

  • the present invention relates to the field of pharmaceutical compounds, and in particular, the present invention discloses a 2-(substituted phenylamino)benzoic acid compound represented by the following formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvent.
  • a pharmaceutical composition for treating leukemia is disclosed.
  • Leukemia is a malignant disease that originates from hematopoietic (lymphatic) stem cells.
  • hematopoietic stem cells A large number of morphologically abnormal leukemia cells are present in the blood, bone marrow, and various tissues and organs of the patient. This kind of cells continue to proliferate and inhibit normal hematopoietic function. Patients will develop a series of symptoms, such as anemia, hemorrhage and different degrees of swelling of the liver and spleen lymph nodes.
  • Fto is an important oncogene in the pathogenesis of leukemia, and knocking down the Fto gene or reducing the expression of FTO protein can effectively inhibit the proliferation of leukemia cells.
  • the object of the present invention is to design and synthesize a series of inhibitors specifically targeting FTO to achieve the purpose of treating leukemia by inhibiting FTO enzymatic function or FTO-mediated signaling process.
  • the pharmaceutically acceptable salt is selected from the group consisting of inorganic acid salts, organic acid salts, inorganic alkali salts, or organic base salts.
  • the pharmaceutically acceptable salt is an alkali metal salt, preferably a lithium salt, a sodium salt or a potassium salt.
  • the inorganic acid salt is selected from the group consisting of a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, a hydrogen sulfate, a nitrate, a phosphate, an acid phosphate;
  • the salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, Lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, besylate, salicylate, picrate, glutamate, salicylate, ascorbic acid Salt, camphorate, camphor sulfonate.
  • the pharmaceutical composition further comprises a second therapeutic agent.
  • the second therapeutic agent is selected from the group consisting of all-trans retinoic acid, alpha-ketoglutarate, an IDH inhibitor (such as an AG-221 inhibitor), and the like.
  • a pharmaceutical composition comprising a compound of formula I as described in the first aspect of the invention, and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof The use of treating leukemia.
  • the pharmaceutical composition further comprises a second therapeutic agent.
  • the second therapeutic agent is selected from the group consisting of all-trans retinoic acid, alpha-ketoglutarate, an IDH inhibitor (such as an AG-221 inhibitor), and the like.
  • the invention provides a method of treating leukemia, the method comprising the steps of: administering to a subject a therapeutically effective amount of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, hydrated , solvate or prodrug.
  • the treating process further comprises administering a second therapeutic agent to the subject.
  • the second therapeutic agent is selected from the group consisting of all-trans retinoic acid, alpha-ketoglutarate, an IDH inhibitor (such as an AG-221 inhibitor), and the like.
  • the inventors have conducted long-term and intensive studies to form a compound of the formula (I) which is capable of efficiently inhibiting the activity of the FTO protein, and thus can be used for the preparation of a pharmaceutical composition for treating leukemia. Based on the above findings, the inventors completed the present invention.
  • substituted means that one or more hydrogen atoms on a group are substituted with a substituent selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy group, halogen, hydroxyl group, carboxyl group (-COOH), C 1 -C 10 aldehyde group, C 2 -C 10 acyl group, C 2 -C 10 ester group, amino group, phenyl group;
  • the phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 10 alkyl, cyano, OH, nitro, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, amino.
  • C 1 -C 6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Base, tert-butyl, or the like.
  • C 1 -C 6 alkoxy refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy. , isobutoxy, sec-butoxy, tert-butoxy, or the like.
  • carbonyl C 1 -C 6 alkyl refers to a group of the formula "-COO-1 to 6 carbon atoms of a straight or branched alkyl group", for example, carbonyl-methyl, carbonyl-ethyl, carbonyl- Propyl, carbonyl-isopropyl, carbonyl-butyl, carbonyl-isobutyl, carbonyl-sec-butyl, carbonyl-tert-butyl, or the like.
  • C 6 -C 12 aryl refers to an aryl group having 6 to 12 carbon atoms, including a monocyclic or bicyclic aryl group such as a phenyl group, a naphthyl group, or the like.
  • 3-12 membered heterocyclyl refers to a saturated or unsaturated (including aromatic) ring system having from 3 to 12 members having one or more heteroatoms selected from O, S, N or P.
  • the group such as pyridyl, thienyl, piperidinyl, or the like, is preferably a 4-9 membered heterocyclic group.
  • halogen refers to F, Cl, Br and I.
  • the terms "containing”, “comprising” or “including” mean that the various ingredients may be used together in the mixture or composition of the present invention. Therefore, the terms “consisting mainly of” and “consisting of” are encompassed by the term “included.”
  • the term "pharmaceutically acceptable” ingredient means a substance which is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reaction), that is, a reasonable benefit/risk ratio.
  • the term "effective amount" means an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect.
  • the precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount that the clinician can determine.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted. Substituted or halogenated C2-C6 acyl, unsubstituted or halogenated C1-C6 alkyl-hydroxy.
  • each of the chiral carbon atoms may be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • compound of the invention refers to a compound of formula I.
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
  • the present invention provides a compound represented by the following formula (I), and a pharmaceutically acceptable salt thereof and a prodrug thereof,
  • the pharmaceutically acceptable salt is preferably a mineral acid salt or an organic acid salt
  • the inorganic acid salt is selected from the group consisting of a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a sulfate salt, a hydrogen sulfate salt, and a nitrate salt.
  • the organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, propylene Acid salt, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, besylate, salicylate, picric acid Salt, glutamate, salicylate, ascorbate, camphorate, camphor sulfonate.
  • the compound of the present invention has excellent inhibitory activity against FTO protein
  • the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are mainly active.
  • the pharmaceutical composition of the ingredients can be used to treat, prevent, and alleviate diseases associated with FTO activity or expression levels. According to the prior art, the compounds of the invention are useful in the treatment of leukemia.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 5 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the present invention provides a new class of FTO protein activity inhibitor, said inhibitor may be very low concentrations (IC 50 value generally below 30 uM) inhibition of the activity of the protein FTO.
  • the FTO inhibitor has high selectivity and has only an inhibitory effect on FTO demethylase, and does not inhibit other homologous or superfamily dioxygenase.
  • the FTO inhibitor described has FTO targeting at the cellular level.
  • the FTO protein activity inhibitor of the present invention exhibits a good pharmacokinetic effect in a mouse leukemia in vivo model, and effectively improves the survival rate of the mouse after administration.
  • the experimental reagents in the experiment were mainly purchased from China National Medicine Corporation, sigma and Shanghai Shenggong.
  • the enzyme reaction system was as follows: 50 mM Tris.HCl, pH 7.5, 0.3 ⁇ M FTO, 1 ⁇ M 39 nt-m 6 A-ssDNA, 300 ⁇ M 2 OG, 280 ⁇ M (NH 4 ) 2 Fe(SO 4 ) 2 , 2 mM L-Ascorbic Acid and different The compound was incubated at room temperature for 2 h, then slowly inactivated at 65 ° C, and an antisense strand of 1 ⁇ M of 39 nt was annealed to form a double strand.
  • Compound IC 50 ( ⁇ M) Compound IC 50 ( ⁇ M) 1 0.7 2 7.6 3 30-50 4 30-50 5 4.6 6 30-50 7 30-50 8 30-50 9 30-50 10 1.2 11 30-50 12 30-50 13 30-50 14 30-50 15 0.06 16 30-50 17 1.14 18 30-50 19 30-50 20 30-50 twenty one 30-50 twenty two 30-50 twenty three 30-50 twenty four 30-50 25 1.6 26 0.4 27 1.1
  • the inhibitory activity of the compounds of the present application is significantly improved, and the FTO inhibitory activity of some compounds can even reach the nmol level.
  • the leukemia cell lines NB4 and MM6 cells were cultured and seeded into 96-well plates at a density of 5,000 per well. After treatment with different compounds for 72 hours, they were directly added to the MTS solution for 10 h to incubate for 4 h. The A490 value was measured and the DMSO group was used as a control. Inhibition rate.
  • the following is the cytotoxicity, i.e., inhibition rate, of the 2-(substituted phenylamino)benzoic acid compound FTO inhibitor represented by the general formula (I) on NB4 and MM6 cells at a concentration of 50 ⁇ M and 72 h.
  • NB4 cells Compound Inhibition rate (MM6 cells) 2 25% 29% 5 39% 46% 15 70% 75% 17 20% 18% 25 100% 100% 26 26% twenty three% 27 100% 100%
  • MM6 cells of IC 50 were 10.4 ⁇ 0.2 ⁇ M and 1.5 ⁇ 0.9 ⁇ M; compound 27 at 48h and 72h on NB4 cells and IC 50 were 6.3 ⁇ 0.1 ⁇ M and 5.3 ⁇ 0.3 ⁇ M, the IC 50 of the MM6 cells were 9.9 ⁇ 0.2 ⁇ M and 5.8 ⁇ 0.2 ⁇ M.
  • MONOMAC 6 is derived from acute myeloid leukemia (AML, FAB, M5) and carries the MLL-AF9 fusion gene.
  • FTO inhibitor compound 25 can significantly inhibit the viability and proliferation of MONOMAC 6 cells, induce apoptosis, and promote ATRA-induced cell differentiation.
  • NGS NOD/LtSz-scid IL2RG–SGM3 mice were produced by hybridization of NOD-scid IL2r ⁇ null (NSG) and NOD/LtSz-scid-SGM3 (NSS). Compared with NSG and NSS mice, it has higher transplantation efficiency.
  • MONOMAC 6 cells Normally cultured MONOMAC 6 cells were injected into the 6-8 week old NSGS mice via the tail vein, and each mouse was injected with 0.2 ⁇ 10 6 cells. After 10 days, the peripheral blood was taken to detect the transplantation efficiency of 20%, and compound 25 (2 mg/kg) was intraperitoneally injected for 10 consecutive days. The control group was intraperitoneally injected with DMSO. NSGS mice showed typical symptoms of leukemia, and they were sacrificed after 20% weight loss. The liver, spleen and bone marrow samples were examined by flow cytometry.
  • the average spleen weight of the mice in the control group was 55 mg, and the average spleen weight of the mice in the administration group was 18 mg.
  • the average liver weight of the control mice was 2200 mg, and the average liver weight of the mice in the administration group was 800 mg.
  • Compound 25 can significantly prolong the survival time of AML mice, and can effectively improve the liver and spleen enlargement of mice with leukemia.

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Abstract

The present invention provides a use of 2-(substituted phenylamino)benzoic acid FTO inhibitor in treating leukemia.

Description

2-(取代苯氨基)苯甲酸类FTO抑制剂治疗白血病的用途Use of 2-(substituted phenylamino)benzoic acid FTO inhibitors for treating leukemia 技术领域Technical field
本发明涉及药物化合物领域，具体地，本发明公开了具有如下通式(I)所示的2-(取代苯氨基)苯甲酸类化合物及其药学上可以接受的盐或药学上可以接受的溶剂合物作为治疗白血病的药物组合物的用途。The present invention relates to the field of pharmaceutical compounds, and in particular, the present invention discloses a 2-(substituted phenylamino)benzoic acid compound represented by the following formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvent. Use of the compound as a pharmaceutical composition for treating leukemia.
背景技术Background technique
白血病是一类起源于造血(淋巴)干细胞的恶性疾病。患者血液、骨髓里以及各种组织器官里都存在着大量形态异常的白血病细胞。这种细胞不断增生，抑制正常造血功能，患者会出现一系列症状，常见贫血、出血和肝脾淋巴结不同程度肿大等临床表现。Leukemia is a malignant disease that originates from hematopoietic (lymphatic) stem cells. A large number of morphologically abnormal leukemia cells are present in the blood, bone marrow, and various tissues and organs of the patient. This kind of cells continue to proliferate and inhibit normal hematopoietic function. Patients will develop a series of symptoms, such as anemia, hemorrhage and different degrees of swelling of the liver and spleen lymph nodes.
最新研究表明，Fto是白血病发病过程中一个重要的致癌基因，而敲低Fto基因或降低FTO蛋白的表达则能够有效抑制白血病细胞的增殖。Recent studies have shown that Fto is an important oncogene in the pathogenesis of leukemia, and knocking down the Fto gene or reducing the expression of FTO protein can effectively inhibit the proliferation of leukemia cells.
综上所述，本领域迫切需要开发特异性靶向FTO的小分子抑制剂。In summary, there is an urgent need in the art to develop small molecule inhibitors that specifically target FTO.
发明内容Summary of the invention
本发明的目的是设计并合成验证了系列特异性靶向FTO的抑制剂，通过抑制FTO酶学的功能或FTO介导的信号过程来达到治疗白血病的目的。The object of the present invention is to design and synthesize a series of inhibitors specifically targeting FTO to achieve the purpose of treating leukemia by inhibiting FTO enzymatic function or FTO-mediated signaling process.
本发明的第一方面，提供了一种如下式(I)所示的化合物，及其药学上可接受的盐，水合物，溶剂合物或前药的用途，其特征在于，用于制备治疗或预防白血病的药物组合物：According to a first aspect of the present invention, there is provided a use of a compound of the formula (I), and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for use in the preparation of a treatment Or a pharmaceutical composition for preventing leukemia:
Figure PCTCN2018077789-appb-000001
Figure PCTCN2018077789-appb-000001
其中，所述的化合物选自下组：Wherein the compound is selected from the group consisting of:
Figure PCTCN2018077789-appb-000002
Figure PCTCN2018077789-appb-000002
在另一优选例中，所述的药学上可接受的盐选自下组：无机酸盐、有机酸盐、无机碱盐，或有机碱盐。In another preferred embodiment, the pharmaceutically acceptable salt is selected from the group consisting of inorganic acid salts, organic acid salts, inorganic alkali salts, or organic base salts.
在另一优选例中，所述的药学上可接受的盐为碱金属盐，优选为锂盐、钠盐或钾盐。In another preferred embodiment, the pharmaceutically acceptable salt is an alkali metal salt, preferably a lithium salt, a sodium salt or a potassium salt.
在另一优选例中，所述无机酸盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；所述有机酸盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、苦味酸盐、谷氨酸盐、水杨酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐。In another preferred embodiment, the inorganic acid salt is selected from the group consisting of a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, a hydrogen sulfate, a nitrate, a phosphate, an acid phosphate; The salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, Lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, besylate, salicylate, picrate, glutamate, salicylate, ascorbic acid Salt, camphorate, camphor sulfonate.
在另一优选例中，所述的药物组合物还包括第二治疗剂。In another preferred embodiment, the pharmaceutical composition further comprises a second therapeutic agent.
在另一优选例中，所述的第二治疗剂选自下组：全反式维甲酸，α-酮戊二酸、IDH抑制剂(如AG-221抑制剂)等。In another preferred embodiment, the second therapeutic agent is selected from the group consisting of all-trans retinoic acid, alpha-ketoglutarate, an IDH inhibitor (such as an AG-221 inhibitor), and the like.
本发明的第二方面，提供了一种药物组合物，包括如本发明第一方面所述的式I化合物，及其药学上可接受的盐，水合物，溶剂合物或前药的用于治疗白血病的用途。In a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula I as described in the first aspect of the invention, and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof The use of treating leukemia.
在另一优选例中，所述的药物组合物还包括第二治疗剂。In another preferred embodiment, the pharmaceutical composition further comprises a second therapeutic agent.
在另一优选例中，所述的第二治疗剂选自下组：全反式维甲酸，α-酮戊二酸、IDH抑制剂(如AG-221抑制剂)等。In another preferred embodiment, the second therapeutic agent is selected from the group consisting of all-trans retinoic acid, alpha-ketoglutarate, an IDH inhibitor (such as an AG-221 inhibitor), and the like.
本发明的第三方面，提供了一种治疗白血病的方法，所述方法包括步骤：对治疗对象施用治疗有效量的如权利要求1所述的式I化合物或其药学上可接受的盐，水合物，溶剂合物或前药。In a third aspect, the invention provides a method of treating leukemia, the method comprising the steps of: administering to a subject a therapeutically effective amount of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, hydrated , solvate or prodrug.
在另一优选例中，所述的治疗过程中，还包括对所述的对象施用第二治疗剂。In another preferred embodiment, the treating process further comprises administering a second therapeutic agent to the subject.
在另一优选例中，所述的第二治疗剂选自下组：全反式维甲酸，α-酮戊二酸、IDH抑制剂(如AG-221抑制剂)等。In another preferred embodiment, the second therapeutic agent is selected from the group consisting of all-trans retinoic acid, alpha-ketoglutarate, an IDH inhibitor (such as an AG-221 inhibitor), and the like.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
具体实施方式detailed description
本发明人经过长期而深入的研究，形如式(I)所示的一类化合物能够高效地抑制FTO蛋白的活性，进而可以用于制备治疗白血病的药物组合物。基于上述发现，发明人完成了本发明。The inventors have conducted long-term and intensive studies to form a compound of the formula (I) which is capable of efficiently inhibiting the activity of the FTO protein, and thus can be used for the preparation of a pharmaceutical composition for treating leukemia. Based on the above findings, the inventors completed the present invention.
术语the term
除非特别说明，在本文中，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：C 1～C 10烷基、C 3～C 10环烷基、C 1～C 10烷氧基、卤素、羟基、羧基(-COOH)、C 1～C 10醛基、C 2～C 10酰基、C 2～C 10酯基、氨基、苯基；所述的苯基包括未取代的苯基或具有1-3个取代基的取代苯基，所述取代基选自：卤素、C 1-C 10烷基、氰基、OH、硝基、C 3～C 10环烷基、C 1～C 10烷氧基、氨基。 Unless otherwise specified, the term "substituted" as used herein means that one or more hydrogen atoms on a group are substituted with a substituent selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy group, halogen, hydroxyl group, carboxyl group (-COOH), C 1 -C 10 aldehyde group, C 2 -C 10 acyl group, C 2 -C 10 ester group, amino group, phenyl group; The phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 10 alkyl, cyano, OH, nitro, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, amino.
术语“C 1～C 6烷基”指具有1～6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。 The term "C 1 -C 6 alkyl" refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Base, tert-butyl, or the like.
术语“C 1～C 6烷氧基”指具有1-6个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。 The term "C 1 -C 6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy. , isobutoxy, sec-butoxy, tert-butoxy, or the like.
术语“羰基C 1～C 6烷基”指形如“-COO-1～6个碳原子的直链或支链烷基”的基团，例如羰基-甲基、羰基-乙基、羰基-丙基、羰基-异丙基、羰基-丁基、羰基-异丁基、羰基-仲丁基、羰基-叔丁基、或类似基团。 The term "carbonyl C 1 -C 6 alkyl" refers to a group of the formula "-COO-1 to 6 carbon atoms of a straight or branched alkyl group", for example, carbonyl-methyl, carbonyl-ethyl, carbonyl- Propyl, carbonyl-isopropyl, carbonyl-butyl, carbonyl-isobutyl, carbonyl-sec-butyl, carbonyl-tert-butyl, or the like.
术语“C 6～C 12芳基”指具有6～12个碳原子的芳基，包括单环或二环芳基，例如苯基、萘基，或类似基团。 The term "C 6 -C 12 aryl" refers to an aryl group having 6 to 12 carbon atoms, including a monocyclic or bicyclic aryl group such as a phenyl group, a naphthyl group, or the like.
术语“3-12元杂环基”指具有3-12元的环系上具有一个或多个选自O、S、N或P的杂原子的饱和或非饱和(包括芳香性)环系取代基，如吡啶基、噻吩基、哌啶基，或类似基团，优选为4-9元的杂环基。The term "3-12 membered heterocyclyl" refers to a saturated or unsaturated (including aromatic) ring system having from 3 to 12 members having one or more heteroatoms selected from O, S, N or P. The group, such as pyridyl, thienyl, piperidinyl, or the like, is preferably a 4-9 membered heterocyclic group.
术语“卤素”指F、Cl、Br和I。The term "halogen" refers to F, Cl, Br and I.
本发明中，术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含 有”中。In the present invention, the terms "containing", "comprising" or "including" mean that the various ingredients may be used together in the mixture or composition of the present invention. Therefore, the terms "consisting mainly of" and "consisting of" are encompassed by the term "included."
本发明中，术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)，即有合理的效益/风险比的物质。In the present invention, the term "pharmaceutically acceptable" ingredient means a substance which is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reaction), that is, a reasonable benefit/risk ratio.
本发明中，术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量，或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此，预先指定准确的有效量是没用的。然而，对于某给定的状况而言，可以用常规实验来确定该有效量，临床医师是能够判断出来的。In the present invention, the term "effective amount" means an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect. The precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount that the clinician can determine.
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C2-C6酰基、未取代或卤代的C1-C6烷基-羟基。As used herein, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted. Substituted or halogenated C2-C6 acyl, unsubstituted or halogenated C1-C6 alkyl-hydroxy.
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的光学异构体，如单一手性的化合物，或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。Unless otherwise stated, all compounds appearing in the present invention are meant to include all possible optical isomers, such as a single chiral compound, or a mixture of various chiral compounds (i.e., racemates). Among all the compounds of the present invention, each of the chiral carbon atoms may be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
如本文所用，术语“本发明化合物”指式I所示的化合物。该术语还包括及式I化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。The term "compound of the invention" as used herein refers to a compound of formula I. The term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
式I化合物Compound of formula I
本发明提供了一种如下式(I)所示的化合物，及其药学上可接受的盐及其前药，The present invention provides a compound represented by the following formula (I), and a pharmaceutically acceptable salt thereof and a prodrug thereof,
Figure PCTCN2018077789-appb-000003
Figure PCTCN2018077789-appb-000003
其中，所述式I化合物选自下组：Wherein the compound of formula I is selected from the group consisting of:
Figure PCTCN2018077789-appb-000004
Figure PCTCN2018077789-appb-000004
所述的药学上可接受的盐优选为无机酸盐或有机酸盐，且所述无机酸盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；所述有机酸盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、苦味酸盐、谷氨酸盐、水杨酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐。The pharmaceutically acceptable salt is preferably a mineral acid salt or an organic acid salt, and the inorganic acid salt is selected from the group consisting of a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a sulfate salt, a hydrogen sulfate salt, and a nitrate salt. , phosphate, acid phosphate; the organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, propylene Acid salt, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, besylate, salicylate, picric acid Salt, glutamate, salicylate, ascorbate, camphorate, camphor sulfonate.
药物组合物和施用方法Pharmaceutical composition and method of administration
由于本发明化合物具有优异的对FTO蛋白的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由与FTO活性或表达量相关的疾病。根据现有技术，本发明化合物可用于治疗白血病。Since the compound of the present invention has excellent inhibitory activity against FTO protein, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are mainly active. The pharmaceutical composition of the ingredients can be used to treat, prevent, and alleviate diseases associated with FTO activity or expression levels. According to the prior art, the compounds of the invention are useful in the treatment of leukemia.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明 显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。The pharmaceutical compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. By "safe and effective amount" it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. In general, the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent. Preferably, the "one dose" is a capsule or tablet.
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂
Figure PCTCN2018077789-appb-000005
润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By "compatibility" it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid). , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier
Figure PCTCN2018077789-appb-000005
Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, hard Calcium citrate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。In addition to these inert diluents, the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants. The active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When a pharmaceutical composition is used, a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight, The dose to be administered is usually from 1 to 2000 mg, preferably from 5 to 500 mg. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
本发明的主要优点包括：The main advantages of the invention include:
(1)本发明提供了一类全新的FTO蛋白活性抑制剂，所述的抑制剂可以在非常低的浓度(IC 50值通常低于30μM)下抑制FTO蛋白的活性。 (1) The present invention provides a new class of FTO protein activity inhibitor, said inhibitor may be very low concentrations (IC 50 value generally below 30 uM) inhibition of the activity of the protein FTO.
(2)较好的安全性。(2) Better security.
(3)所述的FTO抑制剂具有高选择性，只对FTO去甲基化酶有抑制效果，对其他同家族或者是超家族双加氧酶并不产生抑制作用。(3) The FTO inhibitor has high selectivity and has only an inhibitory effect on FTO demethylase, and does not inhibit other homologous or superfamily dioxygenase.
(4)所述的FTO抑制剂在细胞水平上具有FTO靶向性。(4) The FTO inhibitor described has FTO targeting at the cellular level.
(5)所述的FTO抑制剂具有血浆稳定性。(5) The FTO inhibitor described has plasma stability.
(6)本发明的FTO蛋白活性抑制剂在小鼠白血病体内模型中表现出良好的药代动力学效应，施用后有效改善了小鼠存活率。(6) The FTO protein activity inhibitor of the present invention exhibits a good pharmacokinetic effect in a mouse leukemia in vivo model, and effectively improves the survival rate of the mouse after administration.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. Experimental methods in which the specific conditions are not indicated in the following examples are generally carried out according to the conditions described in conventional conditions, for example, Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturing conditions. The conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight and parts by weight.
实验中的实验试剂主要购于中国国药集团，sigma和上海生工。The experimental reagents in the experiment were mainly purchased from China National Medicine Corporation, sigma and Shanghai Shenggong.
实施例中提到的化合物编号如下所示：The compound numbers mentioned in the examples are as follows:
Figure PCTCN2018077789-appb-000006
Figure PCTCN2018077789-appb-000006
实施例1 2-(取代苯氨基)苯甲酸类化合物25的制备Example 1 Preparation of 2-(substituted phenylamino)benzoic acid compound 25
从邻碘苯甲酸和4-溴-2,6-二氯苯胺为起始原料，在无水醋酸铜和N-甲基吗啉的作用下发生Ullman偶联，经历酯化、Suzuki偶联反应，水解以及羟肟酸化可得目标化合物，如下图所示：Starting from o-iodobenzoic acid and 4-bromo-2,6-dichloroaniline, Ullman coupling occurs under the action of anhydrous copper acetate and N-methylmorpholine, and undergoes esterification and Suzuki coupling reaction. , hydrolysis and hydroxamation can obtain the target compound, as shown below:
Figure PCTCN2018077789-appb-000007
Figure PCTCN2018077789-appb-000007
Figure PCTCN2018077789-appb-000008
Figure PCTCN2018077789-appb-000008
将邻碘苯甲酸30g(120mmol,1.2eq)、2,6-二氯-4-溴苯胺24g(100mmol,1.0eq)、三乙胺(150mmol,1.5eq)和无水乙酸铜9g(5.0mmol,0.5eq)溶于DMF 500mL中，氩气保护下加热至120℃反应24h，反应结束后。降温到室温，加入等体积的水，母液用DCM萃取300mL×3，用水洗涤DMF，有机相旋干，过柱比例由PE:EA＝20:1过渡到PE:EA＝1:1得到黄色固体9.8g。30 g (120 mmol, 1.2 eq) of o-iodobenzoic acid, 24 g (100 mmol, 1.0 eq) of 2,6-dichloro-4-bromoaniline, triethylamine (150 mmol, 1.5 eq) and anhydrous copper acetate 9 g (5.0 mmol) , 0.5 eq) was dissolved in DMF 500 mL, heated to 120 ° C under argon atmosphere for 24 h, after the reaction was over. After cooling to room temperature, add an equal volume of water, the mother liquor was extracted with DCM 300 mL×3, DMF was washed with water, the organic phase was spin-dried, and the ratio of the column was changed from PE:EA=20:1 to PE:EA=1:1 to obtain a yellow solid. 9.8g.
Figure PCTCN2018077789-appb-000009
Figure PCTCN2018077789-appb-000009
将2-(4-溴-2,6-二氯苯基)氨基)苯甲酸3.6g溶解于无水乙醇200mL中，冰水浴冷却下，向其中加入浓硫酸20mL，加热至100℃回流反应12小时。反应结束后，反应体系冷却至室温，旋蒸浓缩除去乙醇，向体系中加水100mL，饱和碳酸钠中和不产生气泡为止。乙酸乙酯萃取有机相50mL×3，合并有机相并用饱和食盐水洗涤10mL×3。无水硫酸钠干燥有机相，过滤，滤液浓缩，硅胶层析柱分离，得白色固体2-(4-溴-2,6-二氯苯基)氨基)苯甲酸乙酯3.1g。 1H NMR(400MHz,CDCl 3)δ9.40(s,1H),8.04(d,J＝8.0Hz,1H),7.60–7.77(d,2H),7.36–7.25(m,1H),6.82(t,J＝7.6Hz,1H),6.36(m,1H),4.42(q,J＝7.1Hz,2H),1.45(t,J＝7.1Hz,3H). 3.6 g of 2-(4-bromo-2,6-dichlorophenyl)amino)benzoic acid was dissolved in 200 mL of absolute ethanol, and the mixture was cooled in an ice water bath, and 20 mL of concentrated sulfuric acid was added thereto, and heated to 100 ° C to reflux the reaction 12 hour. After completion of the reaction, the reaction system was cooled to room temperature, and concentrated by evaporation to remove ethanol. Water (100 mL) was added to the system, and saturated sodium carbonate was neutralized to cause no bubbles. The organic phase was extracted with ethyl acetate (50 mL×3), and the organic phase was combined and washed with a saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated. 1 H NMR (400MHz, CDCl 3 ) δ9.40 (s, 1H), 8.04 (d, J = 8.0Hz, 1H), 7.60-7.77 (d, 2H), 7.36-7.25 (m, 1H), 6.82 ( t, J = 7.6 Hz, 1H), 6.36 (m, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H).
Figure PCTCN2018077789-appb-000010
Figure PCTCN2018077789-appb-000010
将2-(4-溴-2,6-二氯苯基)氨基)苯甲酸乙酯3.0g(8.0mmol,1.0eq),2,5-二甲基异恶唑-4-硼酸1.36g(9.6mmol,1.2eq),Pd(dppf)Cl 2 584mg(0.8mmol,0.1eq),碳酸钾1.68g(12.0mmol,1.5eq)溶于二氧六环和水的混合溶剂160mL(4:1/v:v)中，加热至100℃反应24小时。冷却至室温，旋蒸除去一半溶剂，用乙酸乙酯萃取50mL×3，合并有机相并用饱和食盐水洗涤10mL×3。无水硫酸钠干燥有机相，过滤，滤液浓缩，硅胶层析柱分离(石油醚：乙酸乙酯20:1)，得白色固体2-((2,6-二氯-4-(3,5-二甲基异恶唑)苯基)氨基)苯甲酸乙酯1.98g。 1H NMR(500MHz,CDCl 3)δ9.49(s,1H),8.05(dd,J＝8.0,1.5Hz,1H),7.37–7.33(m,1H),7.32(s,2H),6.86–6.81(m,1H),6.44(d,J＝7.7Hz,1H),4.43(q,J＝7.1Hz,2H),2.49(s,3H),2.34(s,3H),1.46(t,J＝7.1Hz,3H). 2-(4-Bromo-2,6-dichlorophenyl)amino)benzoic acid ethyl ester 3.0 g (8.0 mmol, 1.0 eq), 2,5-dimethylisoxazole-4-boronic acid 1.36 g ( 9.6 mmol, 1.2 eq), Pd(dppf)Cl 2 584 mg (0.8 mmol, 0.1 eq), potassium carbonate 1.68 g (12.0 mmol, 1.5 eq) in a mixed solvent of dioxane and water 160 mL (4: 1) In v:v), the mixture was heated to 100 ° C for 24 hours. After cooling to room temperature, half of the solvent was removed by rotary evaporation, and 50 mL×3 was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and then filtered and evaporated to silica gel elute elute Methyl dimethylisoxazole)phenyl)amino)benzoate 1.98 g. 1 H NMR (500 MHz, CDCl 3 ) δ 9.49 (s, 1H), 8.05 (dd, J = 8.0, 1.5 Hz, 1H), 7.37 - 7.33 (m, 1H), 7.32 (s, 2H), 6.86 - 6.81 (m, 1H), 6.44 (d, J = 7.7 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 2.49 (s, 3H), 2.34 (s, 3H), 1.46 (t, J) =7.1Hz, 3H).
Figure PCTCN2018077789-appb-000011
Figure PCTCN2018077789-appb-000011
将2-((2,6-二氯-4-(3,5-二甲基异恶唑)苯基)氨基)苯甲酸乙酯1.98g(4.4mmol,1.0eq)溶于四氢呋喃36mL和无水乙醇72mL的混合溶剂中，冰水浴冷却下，向其中缓缓滴加氢氧化钠880mg(22mmol,5.0eq)的水9mL溶液。加热至45℃反应过夜，反应结束后，体系冷却至室温，浓缩除去有机溶剂，加入水20mL，置于冰水浴中，用稀盐酸2M调节pH至3，所得悬浊液继续在室温下搅拌30min。抽滤，固体用水冲洗，得白色固体2-((2,6-二氯-4-(3,5-二甲基异恶唑)苯基)氨基)苯甲酸1.6g。 1H NMR(400MHz,DMSO)δ13.21(s,1H),9.62(s,1H),7.92(d,J＝7.7Hz,1H),7.68(s,2H),7.37(t,J＝7.6Hz,1H),6.82(t,J＝7.6Hz,1H),6.35(d,J＝8.2Hz,1H),2.47(s,3H),2.29(s,3H). 1.98 g (4.4 mmol, 1.0 eq) of ethyl 2-((2,6-dichloro-4-(3,5-dimethylisoxazole)phenyl)amino)benzoate was dissolved in tetrahydrofuran 36 mL and In a mixed solvent of 72 mL of water ethanol, a solution of 880 mg (22 mmol, 5.0 eq) of water in 9 mL of sodium hydroxide was gradually added dropwise while cooling in an ice water bath. After heating to 45 ° C, the reaction was completed overnight. After the reaction was completed, the system was cooled to room temperature, and the organic solvent was removed by concentration. 20 mL of water was added, and the mixture was placed in an ice water bath. The pH was adjusted to 3 with dilute hydrochloric acid 2M, and the suspension was stirred at room temperature for 30 min. . After suction filtration, the solid was washed with water to yield white crystals of 2-((2,6-dichloro-4-(3,5-dimethylisoxazole)phenyl)amino)benzoic acid 1.6 g. 1 H NMR (400 MHz, DMSO) δ 13.21. (s, 1H), 9.62 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.68 (s, 2H), 7.37 (t, J = 7.6) Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 6.35 (d, J = 8.2 Hz, 1H), 2.47 (s, 3H), 2.29 (s, 3H).
Figure PCTCN2018077789-appb-000012
Figure PCTCN2018077789-appb-000012
将2-(4-溴-2,6-二氯苯基)氨基)苯甲酸844mg(2.2mmol,1.0eq)溶于二氯亚砜22mL中，加热至65℃反应两小时。取样反应液加入无水甲醇中，TLC跟踪反应结束，旋蒸至干的黄色固体酰氯，备用。称取盐酸羟胺152mg(2.2mmol,1.0eq)溶于乙酸乙酯和水的混合液33mL(2:1/v:v)，置于冰水浴中，向其中加入无水碳酸钾608mg(4.4mmol,2.0eq)，室温反应一小时。将新鲜制备的羟胺溶液置于冰水浴中，恒压滴液漏斗缓缓加入酰氯(2.2mmol,1.0eq)的乙酸乙酯10mL溶液，室温反应两小时。旋蒸浓缩，打浆得棕色固体623mg。 1H NMR(400MHz,DMSO)δ11.33(s,1H),9.52(s,1H),9.17(s,1H),7.62(s,2H),7.50(d,J＝7.6Hz,1H),7.26(t,J＝7.8Hz,1H),6.79(t,J＝7.5Hz,1H),6.34(d,J＝8.2Hz,1H),2.44(s,3H),2.26(s,3H). 844 mg (2.2 mmol, 1.0 eq) of 2-(4-bromo-2,6-dichlorophenyl)amino)benzoic acid was dissolved in 22 mL of thionyl chloride and heated to 65 ° C for two hours. The sampled reaction solution was added to anhydrous methanol, and the reaction was quenched by TLC. 152 mg (2.2 mmol, 1.0 eq) of hydroxylamine hydrochloride was dissolved in 33 mL (2:1/v:v) of a mixture of ethyl acetate and water, and placed in an ice water bath, and anhydrous potassium carbonate 608 mg (4.4 mmol) was added thereto. , 2.0 eq), reacted at room temperature for one hour. The freshly prepared hydroxylamine solution was placed in an ice water bath, and a constant pressure dropping funnel was slowly added with a solution of acid chloride (2.2 mmol, 1.0 eq) in ethyl acetate (10 mL) and allowed to react at room temperature for two hours. Concentrated by rotary evaporation and beat to give a brown solid 623mg. 1 H NMR (400MHz, DMSO) δ11.33 (s, 1H), 9.52 (s, 1H), 9.17 (s, 1H), 7.62 (s, 2H), 7.50 (d, J = 7.6Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 2.44 (s, 3H), 2.26 (s, 3H).
其他2-(取代苯氨基)苯甲酸类化合物按与实施例1类似的合成方法，用相应的起始原料进行制备。The other 2-(substituted phenylamino)benzoic acid compounds were prepared in a similar manner to that of Example 1 using the corresponding starting materials.
2-(取代苯氨基)苯甲酸类化合物的氢谱数据：Hydrogen spectrum data of 2-(substituted phenylamino)benzoic acid compounds:
Figure PCTCN2018077789-appb-000013
Figure PCTCN2018077789-appb-000013
Figure PCTCN2018077789-appb-000014
Figure PCTCN2018077789-appb-000014
Figure PCTCN2018077789-appb-000015
Figure PCTCN2018077789-appb-000015
以下为通式(I)所示的2-(取代苯氨基)苯甲酸类化合物抑制FTO酶活性实验。The following is an experiment for inhibiting FTO enzyme activity of a 2-(substituted phenylamino)benzoic acid compound represented by the general formula (I).
生物实施例1 FTO抑制活性测定Biological Example 1 Determination of FTO Inhibitory Activity
通过镍柱亲和层析纯化得到高纯度的FTO蛋白。酶活反应体系如下：50mM Tris.HCl，pH 7.5，0.3μM FTO,1μM 39nt-m 6A-ssDNA,300μM 2OG,280μM(NH 4) 2Fe(SO 4) 2,2mM L-Ascorbic Acid及不同浓度化合物，室温孵育2h后，65℃缓慢加 热失活，加1μM 39nt的反义链DNA退火成双链。取8ul反应液，用甲基化敏感的酶DpnII对双链底物进行酶切，酶切后的样品经15％非变性聚丙烯酰胺电泳检测，Gel-Red染色后凝胶成像系统下拍照，对获得的条带进行灰度的读取，然后进行IC 50值的计算和分析。 Purification by nickel column affinity chromatography yields a high purity FTO protein. The enzyme reaction system was as follows: 50 mM Tris.HCl, pH 7.5, 0.3 μM FTO, 1 μM 39 nt-m 6 A-ssDNA, 300 μM 2 OG, 280 μM (NH 4 ) 2 Fe(SO 4 ) 2 , 2 mM L-Ascorbic Acid and different The compound was incubated at room temperature for 2 h, then slowly inactivated at 65 ° C, and an antisense strand of 1 μM of 39 nt was annealed to form a double strand. 8 ul of the reaction solution was taken, and the double-stranded substrate was digested with a methylation-sensitive enzyme DpnII. The digested sample was detected by 15% non-denaturing polyacrylamide electrophoresis, and the Gel-Red stained gel imaging system was photographed. Gray scale reading is performed on the obtained strip, and then calculation and analysis of IC 50 values are performed.
2-(取代苯氨基)苯甲酸化合物IC 50值： 2-(substituted phenylamino)benzoic acid compound IC 50 value:
化合物Compound IC 50(μM) IC 50 (μM) 化合物Compound IC 50(μM) IC 50 (μM)
11 0.70.7 22 7.67.6
33 30-5030-50 44 30-5030-50
55 4.64.6 66 30-5030-50
77 30-5030-50 88 30-5030-50
99 30-5030-50 1010 1.21.2
1111 30-5030-50 1212 30-5030-50
1313 30-5030-50 1414 30-5030-50
1515 0.060.06 1616 30-5030-50
1717 1.141.14 1818 30-5030-50
1919 30-5030-50 2020 30-5030-50
21twenty one 30-5030-50 22twenty two 30-5030-50
23twenty three 30-5030-50 24twenty four 30-5030-50
2525 1.61.6 2626 0.40.4
2727 1.11.1    
相较于现有的FTO抑制化合物，本申请化合物的抑制活性有非常显著的提升，部分化合物的FTO抑制活性甚至可以达到nmol级。Compared with the existing FTO inhibiting compounds, the inhibitory activity of the compounds of the present application is significantly improved, and the FTO inhibitory activity of some compounds can even reach the nmol level.
生物实施例2 NB4/T(15；17)(NB4)和MONOMAC 6(MM6)细胞毒性测定Biological Example 2 NB4/T (15; 17) (NB4) and MONOMAC 6 (MM6) cytotoxicity assay
以下为通式(I)所示的2-(取代苯氨基)苯甲酸类化合物FTO抑制剂对NB4和MM6细胞毒性IC 50的测定。 The following is a measurement of the cytotoxicity IC 50 of NB4 and MM6 by a 2-(substituted phenylamino)benzoic acid compound FTO inhibitor represented by the general formula (I).
白血病细胞系NB4和MM6细胞经过培养后以5000个每孔的密度种到96孔板中，加入不同的化合物处理72h后，直接加入MTS溶液10uL孵育4h，测A490值,以DMSO组为对照计算抑制率。The leukemia cell lines NB4 and MM6 cells were cultured and seeded into 96-well plates at a density of 5,000 per well. After treatment with different compounds for 72 hours, they were directly added to the MTS solution for 10 h to incubate for 4 h. The A490 value was measured and the DMSO group was used as a control. Inhibition rate.
以下为通式(I)所示的2-(取代苯氨基)苯甲酸类化合物FTO抑制剂在50μM浓度，72h时间点对NB4和MM6细胞的细胞毒性，即抑制率。The following is the cytotoxicity, i.e., inhibition rate, of the 2-(substituted phenylamino)benzoic acid compound FTO inhibitor represented by the general formula (I) on NB4 and MM6 cells at a concentration of 50 μM and 72 h.
化合物Compound 抑制率(NB4细胞)Inhibition rate (NB4 cells) 抑制率(MM6细胞)Inhibition rate (MM6 cells)
22 25％25% 29％29%
55 39％39% 46％46%
1515 70％70% 75％75%
1717 20％20% 18％18%
2525 100％100% 100％100%
2626 26％26% 23％twenty three%
2727 100％100% 100％100%
我们选择了化合物15、25和27对IC 50进行了测定。结果显示，化合物15对NB4 和MM6细胞具有中等毒性，化合物25和化合物27对NB4和MM6细胞均有较强的杀细胞毒性。其中化合物15在72h对NB4和MM6的细胞毒性IC 50分别为44.8±0.5μM和23.6±0.3μM；化合物25在48h和72h对NB4细胞的IC 50分别为4.7±0.3μM和0.8±0.1μM，对MM6细胞的IC 50分别为10.4±0.2μM和1.5±0.9μM；化合物27在48h和72h对NB4细胞的IC 50分别为6.3±0.1μM和5.3±0.3μM，对MM6细胞的IC 50分别为9.9±0.2μM和5.8±0.2μM。 We selected compounds 15, 25 and 27 to determine the IC 50 . The results showed that Compound 15 was moderately toxic to NB4 and MM6 cells, and Compound 25 and Compound 27 had strong cytotoxicity against NB4 and MM6 cells. The cytotoxic IC 50 of compound 15 to NB4 and MM6 at 72 h was 44.8±0.5 μM and 23.6±0.3 μM, respectively; the IC 50 of compound 25 to NB4 cells at 48 h and 72 h was 4.7±0.3 μM and 0.8±0.1 μM, respectively. MM6 cells of IC 50 were 10.4 ± 0.2μM and 1.5 ± 0.9μM; compound 27 at 48h and 72h on NB4 cells and IC 50 were 6.3 ± 0.1μM and 5.3 ± 0.3μM, the IC 50 of the MM6 cells were 9.9 ± 0.2 μM and 5.8 ± 0.2 μM.
生物实施例3 小鼠体内模型试验Biological Example 3 In vivo model test in mice
以下为通式(I)所示的2-(取代苯氨基)苯甲酸类化合物FTO抑制剂对小鼠存活率以及对小鼠脾脏和肝脏的影响。The following are the effects of the 2-(substituted phenylamino)benzoic acid compound FTO inhibitor represented by the general formula (I) on the survival rate of mice and the spleen and liver of mice.
我们选定了化合物25，以2mg/Kg的剂量进行小鼠实验。We selected Compound 25 and performed mouse experiments at a dose of 2 mg/Kg.
MONOMAC 6来源于急性髓系白血病(AML,FAB,M5)，携带有MLL-AF9融合基因。体外实验已经证明FTO抑制剂化合物25能够显著抑制MONOMAC 6细胞的活力和增殖，诱导细胞凋亡，促进ATRA诱导的细胞分化。我们进一步通过体内实验证实化合物25对AML的治疗意义，NOD/LtSz-scid IL2RG–SGM3(NSGS)小鼠是由NOD-scid IL2rγnull(NSG)和NOD/LtSz-scid-SGM3(NSS)杂交产生的，相比于NSG和NSS小鼠具有更高的移植效率。正常培养的MONOMAC 6细胞经尾静脉注射到6-8周的NSGS小鼠体内，每只小鼠注射0.2×10 6细胞。十天天后取外周血检测移植效率达到20％后，连续十天腹腔注射化合物25(2mg/kg)，对照组腹腔注射DMSO。NSGS小鼠表现出典型的白血病症状，体重下降20％后处死，取肝脏、脾脏和骨髓的标本通过流式细胞术检测各组移植效率。 MONOMAC 6 is derived from acute myeloid leukemia (AML, FAB, M5) and carries the MLL-AF9 fusion gene. In vitro experiments have shown that FTO inhibitor compound 25 can significantly inhibit the viability and proliferation of MONOMAC 6 cells, induce apoptosis, and promote ATRA-induced cell differentiation. We further demonstrated the therapeutic significance of compound 25 in AML by in vivo experiments. NOD/LtSz-scid IL2RG–SGM3 (NSGS) mice were produced by hybridization of NOD-scid IL2rγnull (NSG) and NOD/LtSz-scid-SGM3 (NSS). Compared with NSG and NSS mice, it has higher transplantation efficiency. Normally cultured MONOMAC 6 cells were injected into the 6-8 week old NSGS mice via the tail vein, and each mouse was injected with 0.2×10 6 cells. After 10 days, the peripheral blood was taken to detect the transplantation efficiency of 20%, and compound 25 (2 mg/kg) was intraperitoneally injected for 10 consecutive days. The control group was intraperitoneally injected with DMSO. NSGS mice showed typical symptoms of leukemia, and they were sacrificed after 20% weight loss. The liver, spleen and bone marrow samples were examined by flow cytometry.
相对于DMSO组，药物处理组小鼠的肝脏和脾脏肿大的症状受到抑制，同时MONOMAC 6的移植效率也被抑制。实验结果如下表：Compared with the DMSO group, the symptoms of liver and spleen enlargement in the drug-treated group were inhibited, and the transplantation efficiency of MONOMAC 6 was also inhibited. The experimental results are as follows:
Figure PCTCN2018077789-appb-000016
Figure PCTCN2018077789-appb-000016
Figure PCTCN2018077789-appb-000017
Figure PCTCN2018077789-appb-000017
对照组小鼠平均脾重55mg，给药组小鼠平均脾重：18mg。The average spleen weight of the mice in the control group was 55 mg, and the average spleen weight of the mice in the administration group was 18 mg.
对照组小鼠平均肝重2200mg，给药组小鼠平均肝重：800mg。The average liver weight of the control mice was 2200 mg, and the average liver weight of the mice in the administration group was 800 mg.
结果显示，化合物25能够显著延长AML小鼠的存活时间，并且能够有效改善白血病发病小鼠肝脏、脾脏肿大的情况。The results showed that Compound 25 can significantly prolong the survival time of AML mice, and can effectively improve the liver and spleen enlargement of mice with leukemia.
实验结果确定了化合物25对白血病模型具有治疗和改善症状的效果。The experimental results confirmed the effect of Compound 25 on the treatment and improvement of symptoms in the leukemia model.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (10)

  1. 一种如下式(I)所示的化合物，及其药学上可接受的盐，水合物，溶剂合物或前药的用途，其特征在于，用于制备治疗或预防白血病的药物组合物：A use of a compound of the formula (I), and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for the manufacture of a pharmaceutical composition for the treatment or prevention of leukemia:
    Figure PCTCN2018077789-appb-100001
    Figure PCTCN2018077789-appb-100001
    其中，所述的化合物选自下组：Wherein the compound is selected from the group consisting of:
    Figure PCTCN2018077789-appb-100002
    Figure PCTCN2018077789-appb-100002
  2. 如权利要求1所述的用途，其特征在于，所述的药学上可接受的盐选自下组：无机酸盐、有机酸盐、无机碱盐，或有机碱盐。The use according to claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of inorganic acid salts, organic acid salts, inorganic alkali salts, or organic alkali salts.
  3. 如权利要求1所述的用途，其特征在于，所述的药学上可接受的盐为碱金属盐，优选为锂盐、钠盐或钾盐。The use according to claim 1, characterized in that the pharmaceutically acceptable salt is an alkali metal salt, preferably a lithium salt, a sodium salt or a potassium salt.
  4. 如权利要求1所述的用途，其特征在于，所述无机酸盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；所述有机酸盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、苦味酸盐、谷氨酸盐、水杨酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐。The use according to claim 1, wherein the mineral acid salt is selected from the group consisting of a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, a hydrogen sulfate, a nitrate, a phosphate, and an acid phosphate. a salt; the organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate , maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, besylate, salicylate, picrate, glutamate, Salicylate, ascorbate, camphorate, camphor sulfonate.
  5. 如权利要求1所述的药物组合物，其特征在于，所述的药物组合物还包括第二治疗剂。The pharmaceutical composition of claim 1 wherein said pharmaceutical composition further comprises a second therapeutic agent.
  6. 如权利要求1所述的药物组合物，其特征在于，所述的第二治疗剂选自下组：全反式维甲酸，α-酮戊二酸、IDH抑制剂(如AG-221抑制剂)等。The pharmaceutical composition according to claim 1, wherein said second therapeutic agent is selected from the group consisting of all-trans retinoic acid, alpha-ketoglutarate, and IDH inhibitors (such as AG-221 inhibitors). )Wait.
  7. 一种药物组合物，包括如权利要求1所述的式I化合物，及其药学上可接受的盐，水合物，溶剂合物或前药的用于治疗白血病的用途。A pharmaceutical composition comprising a compound of formula I according to claim 1 and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof for use in the treatment of leukemia.
  8. 如权利要求7所述的药物组合物，其特征在于，所述的药物组合物还包括第二治疗剂。The pharmaceutical composition according to claim 7, wherein said pharmaceutical composition further comprises a second therapeutic agent.
  9. 如权利要求7所述的药物组合物，其特征在于，所述的第二治疗剂选自下组：全反式维甲酸，α-酮戊二酸、IDH抑制剂(如AG-221抑制剂)等。The pharmaceutical composition according to claim 7, wherein said second therapeutic agent is selected from the group consisting of all-trans retinoic acid, alpha-ketoglutarate, and IDH inhibitors (such as AG-221 inhibitors). )Wait.
  10. 一种治疗白血病的方法，其特征在于，包括步骤：对治疗对象施用治疗有效量的如权利要求1所述的式I化合物或其药学上可接受的盐，水合物，溶剂合物或前药。A method of treating leukemia, comprising the steps of: administering to a subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, of claim 1. .
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